CN101810562A - Nasal in situ gel containing cortical hormone - Google Patents
Nasal in situ gel containing cortical hormone Download PDFInfo
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- CN101810562A CN101810562A CN200910228790A CN200910228790A CN101810562A CN 101810562 A CN101810562 A CN 101810562A CN 200910228790 A CN200910228790 A CN 200910228790A CN 200910228790 A CN200910228790 A CN 200910228790A CN 101810562 A CN101810562 A CN 101810562A
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Abstract
The invention relates to nasal in situ gel containing cortical hormone, which is prepared from one kind or several kinds of cortical hormone as effective components, environment sensitive type hydrophilic gel materials, other assistant materials acceptable in pharmacy, and water. The preparation comprises 0.01 to 1% of cortical hormone, 0.05 to 40% of environment sensitive type hydrophilic gel materials, and 0.01 to 50% of other assistant materials acceptable in pharmacy.
Description
Technical field:
The present invention relates to a kind of situ-gel that contains 17-hydroxy-11-dehydrocorticosterone.
Background technology:
Allergic rhinitis (allergic rhintis) claim allergic rhinitis again, is the allergic disease of nasal membrane, and can causes multiple complications.Allergic rhinitis can betide any age, the men and women all has, easily see youngster, main cause has: the allergic rhinitis that calendar year 2001 countries in the world expert formulates and to influence (the allergic rhinitis and its impact onasthma.ARIA) guide of asthma, and become The World Health Organization (WHO)) part of proposing, in the ARIA guide, point out, corticosteroid is the most effective medicines of treatment allergic rhinitis, is applicable to that therefrom the severe intermittence is to the treatment of the allergic rhinitis of all degree of middle severe persistence.Different with the 17-hydroxy-11-dehydrocorticosterone of general action, ideal nose should possess following condition (1) receptor affinity (receptor-binding affinity) height, potency (potency) height with 17-hydroxy-11-dehydrocorticosterone; (2) do not influence hypothalamus one hypophysis-adrenal gland's hpa axis (3) Local security height.
As the nose with medicament, because the nasal membrane secreting mucus, the motion of bronchia mucosal cilium has the effect that purifies foreign body and dust on the nasal cavity slime layer, and medicine is eliminated very soon behind the nasal-cavity administration, and bioavailability of medicament is reduced.
Illum L etc. report (Int J Pharm, 1987,39 (3): 189) mucociliary is removed from concha nasalis the medicine that is splashed into the speed of average 5mm/min in the nasal cavity to nasopharynx part, has shortened the contacted time of medicine and mucomembranous surface greatly, directly influences the absorption and the curative effect of medicine.
(allergic rhinitis progress (three): nose is with the pharmacological action of corticosteroid people's report such as to raise, " ear,nose ﹠ throat: head and neck surgery ", 2004 11 1 phases of volume, 67-72, what 22) the medicine systemic bioavailability is played primary effect is the first inactivation ratio of crossing of liver of medicine, under the first excessively situation that inactivation ratio is more or less the same of liver, medicine via intranasal application absorbtivity just seems particularly important.The nasal absorption amount of nasal membrane surface mucociliary clearance system appreciable impact medicine, fat-solubility and low fat-soluble medicine all are difficult for being absorbed.Fat-soluble height and the lower medicine (as: FLUTICASONE PROPIONATE and momestasone furoate) of water solublity, its local dissolution/absorbance is relatively low, the ciliary movement of nasal mucosa surface epithelial cell is pushed medicine to swallow to rear wall fast, make the patient behind the spray medicine, taste the special flavour of medicine usually in 30 seconds, enter gastrointestinal tract by swallowing movement then.It is different with the asal agent type to inhale people's cortex steroid, owing to the transportation function of pulmonary's mucociliary transmission system than nasal cavity a little less than, fat-soluble high medicine is longer in pulmonary's holdup time, can bring into play its pharmacotoxicological effect lentamente.Fat-soluble low and medicine (as: budesonide) that water solublity is higher, its local dissolution/absorbance is higher relatively, and medicine dissolves in the slurry layer of mucociliary transmission system easily, in more easily by Nasal Mucosa Absorption, is also swallowed easily and enters gastrointestinal tract.Therefore improve the time of staying of nasal medicine on the nasal mucosa surface, improve medicine bioavailability become the problem that nasal formulations will solve.
Summary of the invention:
Our surprised by experiment discovery passes through to adopt special gel preparation, can make said preparation in intranasal retention time lengthening, reduce nasal cavital mucus cilium transmission system transporting to medicine, thereby increase the absorption of medicine at the intranasal mucosa, avoid medicine to enter pulmonary, reduce the ratio that medicine is swallowed by gastrointestinal tract, improved the bioavailability of medicine at the intranasal mucosa, can also reduce simultaneously the zest of medicine, avoid the nose ciliary movement fast medicine to be pushed swallow to rear wall preferably, increase especially suitable the being subjected to property of child patient of patient.Also can improve stability of formulation by this preparation simultaneously.Situ-gel (in situ gel) is meant to take place to change the non-chemically crosslinked semi-solid preparation of formation mutually at agents area immediately after the solution state administration.Situ-gel has the hydrophilic three-dimensional net structure and the favorable tissue compatibility of gel preparation, simultaneously, unique solution-gel conversion character make its have concurrently preparation simple, easy to use, with agents area advantages such as particularly the mucous membrane tissue affinity is strong, the holdup time is long, purposes and good control Release Performance widely in addition, the formation mechanism of situ-gel is the response that utilizes macromolecular material to stimulate to external world, make polymer issue the reversible change of diffusing state estranged or conformation, finish by the conversion process of solution to gel at physiological condition.Correspondingly, this special gel can be divided into types such as temperature, ionic strength or pH sensitivity.
For overcoming shortcoming of the prior art, we provide a kind of nasal composition, being of its feature is by making as the water of acceptable auxiliary and surplus on one or more 17-hydroxy-11-dehydrocorticosterone of effective ingredient, environment sensitive type hydrophilic gel material, other pharmaceutics.
The component of preparation consists of: 17-hydroxy-11-dehydrocorticosterone 0.01-1%, environment sensitive type hydrophilic gel material 0.05-40%, acceptable auxiliary 0.01-50% on other pharmaceutics.
Wherein the environmental sensitivity gel is divided into responsive to temperature type, ion-sensitive type, pH responsive type and mixed type.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention is the ion-sensitive type gel, is free-pouring solution at room temperature, and the cation that runs in the snotter forms by cation mediated gel.It is characterized in that described ion-sensitive type hydrophilic gel material is selected from one or more the combination in deacetylation gellan gum, sodium alginate, xanthan gum, welan gum, the carrageenan; preferred deacetylation gellan gum and/or sodium alginate; wherein; the concentration of deacetylation gellan gum is 0.05-2%; the concentration of carrageenan is 0.3-8%; the concentration of welan gum is 0.1-10%, and concentration of xanthan gum is 0.1-10%, and the concentration of sodium alginate is 0.2-9%.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention is the responsive to temperature type gel, is free-pouring solution under the room temperature, and gelling becomes semisolid gel state under the nasal cavity temperature.It is characterized in that described responsive to temperature type hydrophilic gel material is selected from poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA); In N-N-isopropylacrylamide (NiPAAM) copolymer, ethylhydroxyethylcellulose (EHEC) or the xylan one or both and two or more combinations thereof, preferred poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA), wherein, the concentration of poloxamer 407 is 12-40%, the concentration of poloxamer 188 is 5-30%, and the concentration of methylcellulose is 1-10%.The concentration of NiPAAM copolymer is 20-40%, and the concentration of PEG-PLGA is 15-40%, and the concentration of EHEC is 0.1-2%.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention is a pH responsive type gel, pH is free-pouring solution during for 3.5-5.0, acidic-group when pH is elevated to 5.5-6.5 on the polymer chain is neutralized, and electric charge repels mutually and causes strand extension entanglement formation gel.The hydrophilic gel material that it is characterized in that described pH sensitivity is selected from cellulose acetate phthalate ester (CAP), carbomer, the combination in any of one or more in polyethylene acetal diethylamine acetate (AEA), the chitosan, wherein the concentration of CAP is 10-40%, the concentration of carbomer is 0.1-2.0%, and the concentration of chitosan is 1-10%.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention is the mixed type gel, is free-pouring solution under the natural conditions, and physiological condition forms gel down.It is characterized in that described mixed type hydrophilic gel material is the two or more combination in any of responsive to temperature type, pH responsive type, ion-sensitive type macromolecular material, as combinations such as methylcellulose and sodium alginate, poloxamer 407 and sodium alginate, poloxamer 407 and deacetylation gellan gum, poloxamer 407 and carbomers.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention, described pharmaceutically useful adjuvant also comprises osmotic pressure regulator, in gel regulator, antiseptic, pH regulator agent, suspending agent, the wetting agent one or more, and the water of surplus, described osmotic pressure regulator is selected from one or more in mannitol, sorbitol, glycerol, propylene glycol and/or the sodium chloride.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention, its described gel regulator is selected from Polyethylene Glycol (PEG, molecular weight are 6000-11000), polyvidone, sodium citrate, polyoxyethylene, single oleic acid glycerol vinegar, the hydrophilic cellulose base polymer (hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc.) one or more.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention, its described pH regulator agent is an acceptable pH regulator on the pharmaceutics, as sodium hydroxide, triethanolamine, potassium hydroxide, hydrochloric acid etc.Wherein the pH responsive type is adjusted to 3.5-5.0 with the pH value that contains the mixed type gel of pH responsive type material, and the pH value of the gel of other type is adjusted to 5.0-8.0.
17-hydroxy-11-dehydrocorticosterone compositions of the present invention, its described antiseptic are acceptable antiseptic on the pharmaceutics, prick chlorine by in, thimerosal, methyl hydroxybenzoate, ethyl hydroxybenzoate, the propylparaben etc. one or more as chlorobutanol, benzoic acid, benzene.
17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention, its described gel preparation are to pass through nasal-cavity administration with the form of spraying or collunarium.
The present invention also aims to provide a kind of method for preparing the 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, this method comprises and is prepared as follows step: with environment sensitive type hydrophilic gel material abundant swelling in water or in the buffer, respectively acceptable auxiliary on 17-hydroxy-11-dehydrocorticosterone and the pharmaceutics is mixed with solution, environment sensitive type hydrophilic gel material liquid, 17-hydroxy-11-dehydrocorticosterone are mixed with acceptable auxiliary solution on the pharmaceutics, regulate pH value, add water to full dose.Described environment sensitive type hydrophilic gel material is selected from the hydrophilic gel material of ion-sensitive type, responsive to temperature type, pH responsive type and mixed type; Acceptable auxiliary comprises one or more in osmotic pressure regulator, gel regulator, pH regulator agent and the antiseptic on the described pharmaceutics.
Described 17-hydroxy-11-dehydrocorticosterone includes but are not limited to dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone acetonide, fluticasone, mometasone, according to the carbon loteprednol, Rui Meisonglong, fluticasone, beclometasone, ciclesonide, budesonide, methylprednisolone, triamcinolone acetonide, prednicarbate, butixocort (Butixocort), tipredane (Tipredane), one or more of tixocortol (Tixocortol) and their pharmaceutically useful salt or ester or hydrate
In preferred fluticasone propionate, momestasone furoate or its monohydrate, furancarboxylic acid fluticasone, beclomethasone, ciclesonide, budesonide, methylprednisolone aceponate, the triamcinolone acetonide acetate one or more.
The content of 17-hydroxy-11-dehydrocorticosterone is 0.02～1% in the various pharmaceutical composition of the present invention, preferred 0.05～0.2% (weight ratio).Described 17-hydroxy-11-dehydrocorticosterone not soluble in water is preferably made micropowder, and the D90 particle diameter is 0.1～30 μ m, more preferably 0.5-10 μ m.
When described effective ingredient is water-fast 17-hydroxy-11-dehydrocorticosterone micropowder, preferably also contain suspending agent in the described in-situ gel, described suspending agent is one or more in xanthan gum, methylcellulose (MC), tragacanth, arabic gum, pectin, hydroxypropyl emthylcellulose (HPMC) or the sodium carboxymethyl cellulose (CMC-Na).Wherein concentration of xanthan gum is 0.1-6%, the concentration of MC is 1-5%, the concentration of tragacanth is 0.5-4%, the concentration of arabic gum is 5-10%, the concentration of pectin is 1-7%, the concentration of HPMC is 0.1-10%, and the concentration of CMC-Na is 0.5-10%, and needs were selected when concrete concentration can be according to preparation.
When adopting water-fast 17-hydroxy-11-dehydrocorticosterone micropowder in the 17-hydroxy-11-dehydrocorticosterone situ-gel provided by the invention, can when preparation, add wetting agent, the preferred polysorbate esters of described wetting agent (Tween) non-ionic surface active agent.The concentration of polysorbate is 0.1-8wt%.The polysorbate esters is selected from the preferred Tween-80 of Tween-20, Tween-40, Tween-60, Tween-65, Tween-80 and/or Tween-85.
Percentage ratio described in the technical solution of the present invention all is weight percentage
Various pharmaceutical composition of the present invention all is isoosmotic, nasal in-situ gel of the present invention can be made nasal drop, nasal spray, when making nasal spray, can adopt known spray form of medication, use the known quantitative aerosol apparatus that is applicable to nasal administration, the consumption of each spraying is 30 μ L to 150 μ L.
Described environment sensitive type hydrophilic gel material is selected from the hydrophilic gel material of ion-sensitive type, responsive to temperature type, pH responsive type and mixed type; Acceptable auxiliary comprises one or more in osmotic pressure regulator, gel regulator, pH regulator agent and the antiseptic on the described pharmaceutics.
Compared with prior art, adopt 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel of the present invention, owing to adopted the environment sensitive type gel rubber material, make the gel that makes after entering nasal cavity, just undergo phase transition into gel form, can be retained in nasal cavity for more time, realize the continual and steady release of effective ingredient, thereby can improve bioavailability of medicament, reached better therapeutic effect.
The specific embodiment:
Embodiment 1 preparation ion-sensitive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 1):
Table 1 ion-sensitive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription
| Content % | Embodiment 1-1 | Embodiment 1-1 | Embodiment 1-1 | Embodiment 1-1 | Embodiment 1-5 |
| Active constituent content % | Fluticasone propionate 0.05 | Momestasone furoate monohydrate 0.05 | Budesonide 0.1 | Hydrocortisone 1 | Dexamethasone sodium phosphate 0.025 |
| Suspending agent | Xanthan gum 0.15 | Methylcellulose 3 | Arabic gum 5 | ??HPMC?1 | |
| Wetting agent | ??Tween-80??0.1 | ??Tween-80??0.15 | ??Tween-80??0.3 | ??Tween-800.5 | |
| Sodium alginate | ??6 | ??0.8 | |||
| Go acetyl-removed gellan gum | ??0.3 | ??1.2 | ??1.8 | ||
| Osmotic pressure regulator | Glycerol 1.8 | Sorbitol 4.5 | Glycerol 2 | Mannitol 5 | Sodium chloride 0.8 |
| Antiseptic | Chlorobutanol 0.5 | Benzalkonium chloride | Chlorobutanol 0.5 | Hydroxypropyl ethyl ester 0.02 | Hydroxypropyl methyl ester 0.01 |
| The pH regulator agent | HCl transfers pH to 6.2 | HCl transfers pH to 6.2 | HCl transfers pH to 6.2 | HCl transfers pH to 6.2 | HCl transfers pH to 6.2 |
| Water for injection | Surplus | Surplus | Surplus | Surplus | Surplus |
Preparation technology: above-mentioned ion-sensitive type macromolecule is placed proper amount of deionized water, make its dispersing and dissolving in 80-100 ℃ of stirred in water bath, cooling obtains clear and bright solution (1) as for leaving standstill 12h in 4 ℃ of refrigerators.Embodiment 1-1 is mixed in active component micropowder and other water soluble adjuvants to embodiment 1-4 and makes suspension (2) in the water for injection, and (1) and (2) is mixed, and transfers pH to 6.2, adds water to full dose and gets final product.Embodiment 1-5 and other water soluble adjuvants are dissolved in makes solution (2) in the deionized water, (1) and (2) is mixed, and transfers pH to 6.2, adds water to full dose and gets final product.Use Brookfield DV-m type rotating cylinder viscometer under room temperature (20 ℃) condition, to measure the rheological property of above-mentioned five prescriptions.Above-mentioned prescription is along with the increase viscosity of shear rate presents in various degree downward trend, belong to pseudoplastic fluid, embodiment 1-1, embodiment 1-4, embodiment 1-5 viscosity＞250cP, be suitable for using as nasal drop, embodiment 1-2, embodiment 1-3 viscosity＜60cP are suitable for using as nasal spray.Cationic solution according to artificial nose liquid proportional preparation different ions concentration, to mix with it respectively in 32 ℃ of water-baths of above-mentioned 5 embodiment, the point that viscosity enlarges markedly is critical phase transformation cation concn, and result's (seeing Table 5) shows that the critical phase transformation cation concn of above-mentioned 5 prescriptions all is less than or equal to the cation concn of snotter.Therefore estimate that said preparation can form gel at nasal cavity.Under the nasal cavity cation concn, above-mentioned 5 preparations all become glue in 5min.
Embodiment 2 preparation temperature responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gels, write out a prescription following (seeing Table 2):
Table 1 responsive to temperature type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription
| Content % | Embodiment 2-1 | Embodiment 2-1 | Embodiment 2-1 | Embodiment 2-1 |
| Active constituent content % | Fluticasone propionate 0.05 | Momestasone furoate 0.05 | Budesonide 0.1 | Hydrocortisone 1 |
| Poloxamer 407 | ??20 | ??35 | ??12 | |
| Poloxamer 188 | ??5 | ??28 | ??15 | |
| ??PEG(6000-11000) | ??2 | |||
| Polyoxyethylene (PEO) | ??2.5 | |||
| Hydroxypropyl methylcellulose (HPMC) | ??2 | ??1.5 | ||
| Suspending agent | Xanthan gum 0.15 | Arabic gum 5 | ||
| Wetting agent | ??Tween-80??0.1 | ??Tween-80??0.15 | ??Tween-80??0.3 | ??Tween-80??0.5 |
| Osmotic pressure regulator | Sodium chloride 0.9 | Sorbitol 4.5 | Glycerol 2 | Mannitol 5 |
| Antiseptic | Benzalkonium chloride 0.03 | Methyl hydroxybenzoate 0.02 | Chlorobutanol 0.5 | Ethyl hydroxybenzoate 0.05 |
| The pH regulator agent | NaOH transfers pH to 6.5 | Triethanolamine is transferred pH to 6.5 | Triethanolamine is transferred pH to 6.5 | NaOH transfers pH to 6.5 |
| Content % | Embodiment 2-1 | Embodiment 2-1 | Embodiment 2-1 | Embodiment 2-1 |
| Water for injection | Surplus | Surplus | Surplus | Surplus |
Preparation technology:
Said temperature responsive type macromolecule is joined in the cryogenic phosphate buffer (pH6.5), make its dispersing and dissolving under the magnetic agitation, in 4 ℃ of refrigerators, leave standstill 12h and obtain clear and bright solution (1).(HPMC) stirring makes its dissolving, static 12h obtain clear and bright solution (2) under the room temperature for PEG, PEO with the gelling properties regulator.17-hydroxy-11-dehydrocorticosterone micropowder and other water soluble adjuvants be mixed in obtain suspension (3) in the water for injection, three solution mix and stir evenly, and transfer pH to 6.5, add water to full dose and get final product.Use Brookfield DV-III type rotating cylinder viscometer in the rheological property of measuring under room temperature (20 ℃) condition under embodiment 2-1 to the embodiment 2-4 different shear rate.The above-mentioned square everywhere increase viscosity along with shear rate presents downward trend in various degree, belongs to pseudoplastic fluid.Elevated temperature is measured the viscosity under the different temperatures, and the result shows, in nasal cavity (25 ℃-33 ℃) temperature range, and there is tangible phase transition temperature (seeing Table 6) in the temperature that above-mentioned each preparation viscosity all increases in room temperature.Under 32 ℃ of the physiology of the nose temperature, above-mentioned preparation all becomes glue in 2min.
Embodiment 3
Preparation pH responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 3)
Table 3 pH responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription (%)
| Content % | Embodiment 3-1 | Embodiment 3-2 | Embodiment 3-3 |
| Active constituent content % | Fluticasone propionate 0.05 | Momestasone furoate 0.05 | Triamcinolone acetonide 0.1% |
| Cellulose acetate phthalate ester (CAP) | ??30 | ||
| Carbomer 934 | ??0.8 | ||
| Chitosan | ??3 | ||
| Glyceryl monooleate (GMO) | ??3 | ||
| Hydroxypropyl methylcellulose (HPMC) | ??0.5 | ??1 | |
| Suspending agent | Xanthan gum 0.15 | Methylcellulose 3 | Arabic gum 5 |
| Wetting agent | ??Tween-80??0.1 | ??Tween-80??0.15 | ??Tween-80??0.3 |
| Content % | Embodiment 3-1 | Embodiment 3-2 | Embodiment 3-3 |
| Osmotic pressure regulator | Glycerol 1.5 | Glycerol 2 | Sorbitol 4.5 |
| Antiseptic | Benzalkonium chloride 0.03 | Methyl hydroxybenzoate 0.02 | Chlorobutanol 0.5 |
| The pH regulator agent | HCl transfers pH to 4.0 | HCl transfers pH to 4.0 | HCl transfers pH to 4.0 |
| Water for injection | Surplus | Surplus | Surplus |
Preparation method: pH responsive type gel rubber material is dissolved in distilled water, and wherein CAP stirring and dissolving in the HCl of pH3.0 solution leaves standstill 12h and obtains clear and bright solution in 4 ℃ of refrigerators; Carbomer 934 is dissolved in a certain amount of water and obtains solution; Chitosan dissolves in the citric acid solution of 0.33M, leaves standstill 12h and obtain clear and bright solution in 4 ℃ of refrigerators.
17-hydroxy-11-dehydrocorticosterone micropowder and other water soluble adjuvants be mixed in a certain amount of distilled water obtain suspension, the solution that is mixed with gel regulator (HPMC, GMO) mixes, be added dropwise in the responsive gel solution of above-mentioned pH, regulate pH to 4.0, the water that replenishes surplus is to full dose.
Use Brookfield DV-III type rotating cylinder viscometer to measure the rheological property of above-mentioned three prescriptions under different shear rate at ambient temperature.Above-mentioned three prescriptions belong to pseudoplastic fluid along with the increase viscosity of shear rate presents in various degree downward trend.Above-mentioned prescription is mixed with the phosphate buffer of different pH value according to 1: 1 ratio, and in 32 ℃ of mensuration viscosity, the result shows that each preparation is (pH5-6.5) viscosity generation significant change in nasal cavity pH scope, and critical phase transformation pH sees Table 7.Under pH value 6.5 conditions, above-mentioned preparation all becomes glue in 5min.
Embodiment 4
Preparation mixed type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 4)
| Content % | Embodiment 4-1 | Embodiment 4-2 | Embodiment 4-3 | Embodiment 4-4 |
| Active constituent content % | Fluticasone propionate 0.05 | Momestasone furoate 0.05 | Budesonide 0.1% | Hydrocortisone 1% |
| Methylcellulose | ??2 | |||
| Poloxamer 407 | ??18 | ??18 | ??18 | |
| Poloxamer 188 | ??0.3 | ??1.2 | ||
| Carbomer 934 | ??0.5 | |||
| Sodium alginate | ??0.8 | ??0.5 |
| Content % | Embodiment 4-1 | Embodiment 4-2 | Embodiment 4-3 | Embodiment 4-4 |
| Go acetyl-removed gellan gum | ??0.2 | |||
| ??PEG(6000-11000) | ??8 | |||
| Sodium citrate | ??3.2 | |||
| Osmotic pressure regulator | Mannitol 4.5 | Glycerol 2 | Glycerol 2 | Sorbitol 4.5 |
| Antiseptic | Benzalkonium chloride 0.03 | Methyl hydroxybenzoate 0.02 | Chlorobutanol 0.5 | Ethyl hydroxybenzoate 0.05 |
| Suspending agent | Xanthan gum 0.15% | Methylcellulose 3% | Arabic gum 5 % | ??HPMC?1％ |
| Wetting agent | ??Tween-80??0.1％ | ??Tween-80??0.15％ | ??Tween-80??0.3％ | ??Tween-80??0.5％ |
| The pH regulator agent | NaOH transfers pH to 6.5 | Triethanolamine is transferred pH to 6.5 | Triethanolamine is transferred pH to 6.5 | HCl transfers pH to 4.0 |
| Water for injection | Surplus | Surplus | Surplus | Surplus |
Ion-sensitive type gel rubber material (sodium alginate, go acetyl-removed gellan gum) is dissolved in 80-90 ℃ distilled water, in 4 ℃ of refrigerators, leave standstill 12h and obtain clear and bright solution (1), carbomer 934 is scattered in a certain amount of water, abundant swelling, be scattered in the phosphate buffer (pH6.5) under responsive to temperature type (poloxamer 407, the methylcellulose) low temperature, stirring makes its dispersing and dissolving, leaves standstill 12h and obtain clear and bright solution (2) in 4 ℃ of refrigerators.17-hydroxy-11-dehydrocorticosterone micropowder and water soluble adjuvant mix with gel solution after being mixed in and making suspension in the water, regulate pH value by prescription, and the water that replenishes surplus is to full dose.
Use Brookfiekl DV-III type rotating cylinder viscometer under room temperature (20 ℃) condition, to measure the rheological property of above-mentioned four prescriptions under different shear rate.The above-mentioned square everywhere increase viscosity along with shear rate presents downward trend in various degree, belongs to pseudoplastic fluid.
Cationic solution according to artificial nose liquid proportional preparation different ionic strength, embodiment 4-1 to 4-3 is mixed with it respectively, under different temperatures, measure viscosity, the result shows that critical phase transformation cation intensity all is less than or equal to the cation intensity of snotter, critical phase transition temperature is 25 ℃-33 ℃, the results are shown in Table 15.To mix with the phosphate buffer of different pH value according to 1: 1 ratio, and measure viscosity under different temperatures, the result shows that preparation is in pH5.5 place viscosity generation significant change, and critical phase transition temperature is 33.5 ℃.Under physiological condition, each preparation all presents good gelling property, uses separately with the environment sensitive type material that to compare gelation rate fast.
Pharmacology embodiment 1-1: test implementation example 1 gained preparation phase transformation cation concn
Preparation artificial nose liquid adopts to add sodium chloride 7.91g, sodium bicarbonate 2.56g in every 1000ml water.Potassium chloride 3.68g and calcium chloride 0.51g
Adopting above-mentioned electrolyte solution is standard artificial nose liquid, prepares the artificial nose liquid of different ionic strength in proportion, is 1 with the ionic strength of standard artificial nose liquid
With the artificial nose liquid of the gel that obtains and the different ionic strength volume mixture according to 1: 1, viscosity significantly improves 32 ℃ of water-baths, the ionic strength that the becomes gel critical phase transformation cation concn of ascending the throne,
Table 5, the critical phase transformation ionic strength of embodiment 1-1 to 1-5
| Embodiment 1-1 | Embodiment 1-2 | Embodiment 1-3 | Embodiment 1-4 | Embodiment 1-5 | |
| Phase transformation cation intensity (with standard artificial nose liquid cation intensity rate) | ??0.9 | ??0.9 | ??0.5 | ?0.4 | ??0.4 |
Pharmacology embodiment 1-2
Table 6: the critical phase transition temperature of embodiment 2-1 to 2-4 gained preparation
| Embodiment 1-1 | Embodiment 1-2 | Embodiment 1-3 | Embodiment 1-4 | |
| Phase transition temperature | ??29.6℃ | ??27.3℃ | ??30.8℃ | ??28.3℃ |
Pharmacology embodiment 1-3
Table 7: embodiment 3-1 to 3-3 gained preparation critical phase change pH values
| Embodiment 3-1 | Embodiment 3-2 | Embodiment 3-3 | |
| The phase change pH values | ??5.7 | ?5.2 | ?5.6 |
Pharmacology embodiment 1-4
Table 8: the critical phase change conditions of embodiment 4-1 to 4-4 gained preparation
| Embodiment 1-1 | Embodiment 1-2 | Embodiment 1-3 | Embodiment 1-4 | |
| Phase transition temperature | ??26.6℃ | ??33.0℃ | ??30.8℃ | ?33.5℃ |
| Embodiment 1-1 | Embodiment 1-2 | Embodiment 1-3 | Embodiment 1-4 | |
| Phase transformation cation intensity (with standard artificial nose liquid cation intensity rate) | ??0.9 | ??0.9 | ??0.5 | |
| The phase change pH values | ?5.5 |
The research of pharmacology embodiment 2 medicine release in vitro behaviors
With reference to the dissolution determination three therapeutic methods of traditional Chinese medicine under two appendix XC of 2005 editions Pharmacopoeias of the People's Republic of China item, adopt the bag filter method to measure the dissolution of each preparation.Getting the foregoing description gained and be originally each 1ml of gel in bag filter, place in the stripping rotor, is dissolution medium with artificial nose mucus described in the pharmacology embodiment 1, and rotating speed is that per minute 25 changes, respectively at 5,15,30,45,60,90,120,180,240,360, the 480min sampling filters, filtrate is measured absorbance according to ultraviolet one visible spectrophotometry (appendix WA) at wavelength 235nm, calculates the cumulative release degree of medicine.The result shows that above-mentioned preparation all has slow release characteristic, and release reaches more than 80% behind the 3h.And all have the prominent phenomenon of releasing of medicine, this be since during gel gelling on the throne aqueous solution efflux.This feature helps medicine and reaches treatment concentration faster.
Pharmacology embodiment 3 cilium toxicity tests
Employing is the crocodile model on the body frog, and observation by light microscope cilium persistent movement time method is estimated the nasal ciliary toxicity of preparation.The frog is fixed, drip medicinal liquid in last palatine mucosa, flush away after contact a period of time separates mucosa and observes the ciliary movement situation.The result shows that the persistent movement time of nose cilium does not have significant change with after above-mentioned preparation contacts, and cilium comes off less, the mucosa complete form.Illustrate that preparation fibre-less toxicity or toxicity that the embodiment of the invention provides are less.
Claims (10)
1. one or more 17-hydroxy-11-dehydrocorticosterone contain the nasal in situ gel of one or more acceptable accessories, being of its feature is by making as the water of acceptable auxiliary and surplus on one or more 17-hydroxy-11-dehydrocorticosterone of effective ingredient, environment sensitive type hydrophilic gel material, other pharmaceutics.
2. nasal in situ gel as claimed in claim 1 is characterized in that the component of described preparation consists of: 17-hydroxy-11-dehydrocorticosterone 0.01-1%, environment sensitive type hydrophilic gel material 0.05-40%, acceptable auxiliary 0.01-50% on other pharmaceutics.
3. nasal in situ gel as claimed in claim 2; it is characterized in that described preparation is the ion-sensitive type gel; described ion-sensitive type hydrophilic gel material is selected from one or more the combination in deacetylation gellan gum, sodium alginate, welan gum, the carrageenan; the concentration of deacetylation gellan gum is 0.05-2%; the concentration of carrageenan is 0.3-8%; the concentration of welan gum is 0.1-10%, and the concentration of sodium alginate is 0.2-9%.
4. nasal in situ gel as claimed in claim 2, it is characterized in that described preparation is the responsive to temperature type gel, described responsive to temperature type hydrophilic gel material is selected from poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA); In N-N-isopropylacrylamide (NiPAAM) copolymer, ethylhydroxyethylcellulose (EHEC) or the xylan one or both and two or more combinations thereof, the concentration of poloxamer 407 is 12-40%, the concentration of poloxamer 188 is 5-30%, and the concentration of methylcellulose is 1-10%.The concentration of NiPAAM copolymer is 20-40%, and the concentration of PEG-PLGA is 15-40%, and the concentration of EHEC is 0.1-2%.
5. nasal in situ gel as claimed in claim 2, it is characterized in that described preparation is a pH responsive type gel, the hydrophilic gel material of described pH sensitivity is selected from cellulose acetate phthalate ester (CAP), carbomer, the combination in any of one or more in polyethylene acetal diethylamine acetate (AEA), the chitosan, wherein the concentration of CAP is 10-40%, the concentration of carbomer is 0.1-2.0%, the concentration of chitosan is 1-10%, and the pH value of described pH responsive type gel is adjusted to 3.5-5.0.
6. nasal in situ gel as claimed in claim 2, the described preparation of its feature is the mixed type gel, described mixed type hydrophilic gel material is the two or more combination in any of responsive to temperature type, pH responsive type, ion-sensitive type macromolecular material.The pH value of the mixed type gel of the described pH of containing responsive type material is adjusted to 3.5-5.0.
7. as arbitrary described nasal in situ gel in the claim 1 to 6, it is characterized in that described pharmaceutically useful adjuvant also comprises osmotic pressure regulator, one or more in gel regulator antiseptic pH regulator agent suspending agent, the wetting agent, and the water of surplus.
8. as arbitrary described nasal in situ gel in the claim 1 to 7, it is characterized in that described 17-hydroxy-11-dehydrocorticosterone includes but are not limited to dexamethasone, betamethasone, fluorometholone, prednisone, prednisolone, methylprednisolone, hydrocortisone, fluocinolone acetonide, fluticasone, mometasone, according to the carbon loteprednol, Rui Meisonglong, fluticasone, beclometasone, ciclesonide, budesonide, methylprednisolone, triamcinolone acetonide, prednicarbate, butixocort (Butixocort), tipredane (Tipredane), one or more of tixocortol (Tixocortol) and their pharmaceutically useful salt or ester or hydrate, content are 0.02～1%.
9. as arbitrary described nasal in situ gel in the claim 1 to 8, when it is characterized in that described active component is water-fast 17-hydroxy-11-dehydrocorticosterone micropowder, also contain suspending agent in the described in-situ gel, described suspending agent is one or more in xanthan gum, methylcellulose (MC), tragacanth, arabic gum, pectin, hydroxypropyl emthylcellulose (HPMC) or the sodium carboxymethyl cellulose (CMC-Na).Wherein concentration of xanthan gum is 0.1-6%, and the concentration of MC is 1-5%, and the concentration of tragacanth is 0.5-4%, and the concentration of arabic gum is 5-10%, and the concentration of pectin is 1-7%, and the concentration of HPMC is 0.1-10%, and the concentration of CMC-Na is 0.5-10%.
As claim 1 to 9 arbitrary as described in nasal in situ gel, when it is characterized in that described active component is water-fast 17-hydroxy-11-dehydrocorticosterone micropowder, also contain wetting agent in the described in-situ gel, the preferred polysorbate esters of described wetting agent (Tween) non-ionic surface active agent.The concentration of polysorbate is 0.1-8%.
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| CN200910228790A CN101810562A (en) | 2009-11-26 | 2009-11-26 | Nasal in situ gel containing cortical hormone |
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| CN200910228790A CN101810562A (en) | 2009-11-26 | 2009-11-26 | Nasal in situ gel containing cortical hormone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102600250A (en) * | 2011-01-25 | 2012-07-25 | 中国医学科学院药用植物研究所 | In-situ gel sustained-release preparation of Ranunculus ternatus Thunb., and its preparation method |
| CN102743760A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Bacteriostatic agent GellanGum-containing externally-used composite for eyes |
| CN103169649A (en) * | 2013-04-11 | 2013-06-26 | 中国人民解放军总医院 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
| CN104055728A (en) * | 2014-06-16 | 2014-09-24 | 温州医科大学 | Preparation method of ophthalmic triamcinolone acetonide hydrogel preparation |
| EP3047846A1 (en) * | 2015-01-22 | 2016-07-27 | Ems S.A. | Dosage forms containing fluticasone propionate for the treatment of inflammatory conditions of the esophagus |
| US9937258B2 (en) | 2013-07-17 | 2018-04-10 | Dow Global Technologies Llc | Composition for application to a nasal mucosa comprising a methylcellulose |
| CN110101653A (en) * | 2019-04-19 | 2019-08-09 | 珐玛赫(天津)医药科技有限公司 | A kind of nasal cavity situ-gel composition, Its Preparation Method And Use |
| CN114404354A (en) * | 2021-11-12 | 2022-04-29 | 合肥启灏医疗科技有限公司 | Nasal in situ gel preparation and preparation method thereof |
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- 2009-11-26 CN CN200910228790A patent/CN101810562A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102600250A (en) * | 2011-01-25 | 2012-07-25 | 中国医学科学院药用植物研究所 | In-situ gel sustained-release preparation of Ranunculus ternatus Thunb., and its preparation method |
| CN102600250B (en) * | 2011-01-25 | 2013-12-18 | 中国医学科学院药用植物研究所 | In-situ gel sustained-release preparation of Ranunculus ternatus Thunb., and its preparation method |
| CN102743760A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Bacteriostatic agent GellanGum-containing externally-used composite for eyes |
| CN103169649A (en) * | 2013-04-11 | 2013-06-26 | 中国人民解放军总医院 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
| US9937258B2 (en) | 2013-07-17 | 2018-04-10 | Dow Global Technologies Llc | Composition for application to a nasal mucosa comprising a methylcellulose |
| CN104055728A (en) * | 2014-06-16 | 2014-09-24 | 温州医科大学 | Preparation method of ophthalmic triamcinolone acetonide hydrogel preparation |
| CN104055728B (en) * | 2014-06-16 | 2016-10-12 | 温州医科大学 | A kind of preparation method of triamcinolone acetonide hydrogel ophthalmic preparation |
| EP3047846A1 (en) * | 2015-01-22 | 2016-07-27 | Ems S.A. | Dosage forms containing fluticasone propionate for the treatment of inflammatory conditions of the esophagus |
| CN110101653A (en) * | 2019-04-19 | 2019-08-09 | 珐玛赫(天津)医药科技有限公司 | A kind of nasal cavity situ-gel composition, Its Preparation Method And Use |
| CN114404354A (en) * | 2021-11-12 | 2022-04-29 | 合肥启灏医疗科技有限公司 | Nasal in situ gel preparation and preparation method thereof |
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